Adipocytes are highly specialized cells that play a critical role in energy and homeostasis. Their primary role is to store triglycerides in times of caloric excess and to mobilize this reserver during periods of nutritional deprivation. Adipocytes are derived from a multipotent stem cell of mesodermal origin that also gives rise to the muscle and cartilage lineages. Adipocyte differentiation is characterized by a coordinate increase in adipocyte-specific gene expression.
Recent years have seen important advances in our understanding of the molecular basis of adipocyte differentiation. (reviewed in Cornelius, P. et al. (1994) Annu. Rev. Nutr. 14:99-129; Tontonoz, P. et al. (1995) Curr. Opin. Genet. Dev. 5:571-576. A number of transcription factors are induced in fat cell differentiation (C/EBPα, C/EBPβ and ADD1/SREBP1) and influence this process to a certain extent (Freytag, S. O. et al. (1994) Genes Dev. 8:1654-63; Kim, J. B. and Spiegelman, B. M. (1996) Genes Dev. 10:1096-1107; Lin, F. T. and Lane, M. D. (1994) PNAS USA 91:8757-61; Samuelsson, L. et al. (1991) EMBO J. 10:3787-93; Tontonoz, P. et al. (1993) Mol Cell Biol 13:4753-9; Umek, R. M. et al. (1991) Science 251:288-92; Wu, C. L. et al. (1995) Mol Cell Biol 15:253646; Yeh, W. C. et al. (1995) Genes Dev. 9:168-81).
The peroxisome proliferator-activated receptors, or “PPAR”, are members of the type II class of steroid/thyroid superfamily of receptors and which mediate the pleiotropic effects of peroxisome proliferators. Type II class of nuclear receptors includes PPAR, the thyroid hormone receptor (T3R), and the vitamin D3 receptor (VD3R). Type II receptors are functionally distinct from the classical steroid receptors, such as the glucocorticoid receptor, the progesterone receptor and the estrogen receptor (reviewed in Stunnenberg, H. G. (1993) BioEssays Vol. 15 (5): 309-15. Three properties distinguish these two classes. Firstly, type II receptors are able to bind to their responsive elements in the absence of ligand (Damm et al. (1989) Nature 339:593-597; Sap et al., Nature 340:242-244; De The et al. (1990) Nature 343:177-180), whereas ligand binding is required to dissociate to the type I receptor-hsp 90 complex and hence indirectly governs DNA binding. Secondly, type II receptors bind and transactivate through responsive elements that are composed of half-sites arranged as direct repeats, as opposed to palindromically arranged half-sites invariably separated by three nucleotides required by type I receptors. Finally, type II receptors do not bind to their respective binding site as homodimers but require an auxiliary factor, R×R (e.g., R×Rα, R×Rβ, R×Rγ) for high affinity binding (Yu et al. (1991) Cell 67:1251-1266; Bugge et al. (1992) EMBO J. 11:1409-1418; Kliewer et al. (1992) Nature 355:446-449; Leid et al. (1992) Cell 68:377-395; Marks et al. (1992) EMBO J. 11:1419-1435; Zhang et al. (1992) Nature 355:441446). The interaction between type II receptors requires a region in the C-terminal domain (Yu et al. (1991) Cell 67:1251-1266; Kliewer et al. (1992) Nature 355:446-449; Leid et al. (1992) Cell 68:377-395; Marks et al. (1992) EMBO J. 11:1419-1435). Following binding, the transcriptional activity of a target gene (i.e., a gene associated with the specific DNA sequence) is enhanced as a function of the ligand bound to the receptor heterodimer.